POSSIBLE TOXICITIES OF MEDICATIONS AND MEDICATIONS USED TO AVAILABILITY

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MEDICATIONS AND
AVAILABILITY
Trientine
Available as:
■ Syprine® (Trientine Hydrochloride), 250mg
capsules. Merck & Co. Inc. Whitehouse
Station, NJ 08889 U.S.A.
■
A Clinical Tool
For Physicians
“The Wilson’s Disease Association funds research
and facilitates and promotes the identification,
education, treatment, and support of patients and
other individuals affected by Wilson’s Disease.”
For more information
please contact the:
Zinc
Available as:
■ Galzin™ (zinc acetate), 25mg or 50mg
capsules. Gate Pharmaceuticals, Div. of TEVA
Pharmaceuticals USA. Sellersville, PA. 18960
■
Penicillamine:
Trientine dihydrochloride, 300 mg capsules.
Univar Ltd., U.K.
D-Penicillamine
Available as:
■ Cuprimine® (Penicillamine), 125mg or 250 mg
capsules. Merck & Co. Inc. Whitehouse
Station, NJ 08889 U.S.A.
1802 Brookside Drive
Wooster, Ohio 44691
888-264-1450
330-264-1450
wda@sssnet.com
www.wilsonsdisease.org
Wilzin (zinc acetate dihydrate), 25mg or
50mg capsules. Orphan Europe SARL, France
A Diagnosis of
Wilson’s Disease
This brochure has been written to assist you and your
medical advisors. It is not intended to replace any
advice you receive from your treating physician.
POSSIBLE TOXICITIES OF
MEDICATIONS USED TO
TREAT WILSON’S DISEASE
What Now?
References:
Ageusia
Agranulocytosis
Alopecia
Anorexia, epigastric pain, nausea, vomiting,
diarrhea
Aplastic anemia
Blurred vision
Cutaneous macular atrophy
Degenerative changes of the skin (especially of the
neck)
Depression of serum IgA levels
Diplopia
Elastosis perforans serpiginosa – EPS lesions
Goodpasture’s syndrome
Hepatotoxicity
Hyperkeratosis
Hypogeusia
Initial hypersensitivity: hives, rash, fever,
anaphylaxis, lymphadenopathy
Intrahepatic cholestasis
Leukopenia
Lichen planus
Lupus-like reaction
Mammary hyperplasia
Myasthenic syndrome
Nephrotic syndrome
Obliterative bronchitis
Optical axial neuritis
Oral ulcerations
Proteinuria
Ptosis
Serous retinitis
Thrombocytopenia or total aplasia
Brewer, George J. (2001) WILSON’S DISEASE: A
Clinicians Guide to Recognition, Diagnosis, and
Management. Norwell MA: Kluwer Academic
Publishers
Trientine:
Roberts, EA. & Schilsky, ML. (2003) A Practice
Guideline on Wilson Disease. Hepatology, 37(6),
1475-1491.
Zinc:
9/05
Ageusia
Aplastic anemia (rare)
Gastritis
Sideroblastic anemia
TREATMENT AND MANAGEMENT
Biochemical pancreatitis
Gastritis
Leukopenia
Zinc accumulation
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RECOMMENDATIONS UPON CONFIRMED DIAGNOSIS
TREATMENT
MEDICATION GUIDELINES
Goals:
Goal:
Maintenance Treatment
Laboratory Testing:
To maintain copper balance within the optimal
range to avoid copper deposition or overchelation/copper depletion
Adult doses
Trientine – 750-1,000 mg/d in 2 - 3 divided doses.
Tetrathiomolybdate – no current dosing regimen
established, still in clinical trials.
D-Penicillamine – 750-1,000 mg/d in 2 divided doses.
Vitamin B6 (pyroxidine) – 25-50 mg/d taken away
from Penicillamine to prevent B6 deficiency caused
by Penicillamine.
Zinc salts – 150 mg/d in 3 divided doses.
Frequency is variable, but at least twice per year
More frequently is necessary during the initial phase
of treatment, if worsening of symptoms or side
effects of medication occurs, for suspected noncompliance, other interruption or change in therapy.
■
■
To stabilize disease symptoms and biochemical
abnormalities in symptomatic patients
To prevent disease symptoms and biochemical
abnormalities in presymptomatic patients
In Symptomatic Patients:
■ Initiate drug therapy with chelator alone or
in combination with zinc
■ Reduce excess copper deposits
■ Initiate adjunctive evaluations/therapies as
needed: speech, physical, psychiatric,
neurological and hepatic—including for
portal hypertension, ascites or edema.
■ Transplant evaluation if necessary
In Presymptomatic Patients:
■ Initiate drug therapy with zinc
■ Reduce or prevent excess copper deposits
Diet:
Initial Phase:
■ Generally, avoid foods with very high copper
content: shellfish, nuts, chocolate,
mushrooms, organ meat.
■ Practicing vegetarians should consult a dietician
■ Avoid copper cookware
■ Avoid vitamin/dietary supplements
containing copper, as well as mineral water
■ Check copper content of household water for
cooking or consumption, especially well water,
or if brought in through copper pipes. Flush
system of stagnant water before such use. A
water purifying system may be advisable for
high levels of copper (over 0.1 ppm)
Maintenance Phase:
■ May be more liberal than in the initial phase
of treatment, based on response to therapy
■ Avoid organ meat and excessive shellfish
consumption
■ Careful evaluation of dietary supplements
and nutraceuticals
Medications:
Chelators – Usually the initial treatment
recommended for symptomatic patients
■ Trientine – Induces cupriuria
■ D-Penicillamine – Induces cupriuria (Not
recommended for patients presenting with
neurological symptoms)
■ Tetrathiomolybdate – Induces cupriuria and
intestinal copper loss. Also blocks copper
absorption. (As of this time, still experimental
in U.S. and Canada)
Metallothionein inducer – A cellular protein that
binds copper and blocks intestinal absorption of
copper. Rarely used alone as initial treatment in
symptomatic patients.
■ Zinc salts – Blocks intestinal absorption of
copper. (Must contain exactly 25 or 50mg of
elemental zinc in combination with a salt)
Pediatric doses
Same as for Initial Phase until >50kg body weight
Medications must be taken daily, as prescribed, with
water only, at least 1 hour before or after food
consumption for proper absorption. Therapy must
not be interrupted and must continue lifelong.
Maintenance phase: Typically 6-12 months after
initiation of therapy when copper levels and lab
values have begun to normalize.
Initial Treatment
MONITORING OF WILSON’S
DISEASE THERAPY
Adult doses
Goals:
Trientine – 750-1,500 mg/d in 2 – 4 divided doses.
Tetrathiomolybdate – no current dosing regimen
established, still in clinical trials.
D-Penicillamine – 1,000-1,500 mg/d in 2 – 4 divided
doses. Vitamin B6 (pyroxidine) – 25-50 mg/d taken
away from Penicillamine to prevent B6 deficiency
caused by Penicillamine.
Zinc salts – 150 mg/d in 3 divided doses.
The importance of monitoring for patient adherence
and efficacy of therapy cannot be overemphasized.
Pediatric doses (<50 kg body weight)
Physical Exams:
Trientine – 20 mg/kg/d, rounded to nearest 250mg in
2 or 3 divided doses
Tetrathiomolybdate – not established
D-Penicillamine – 20 mg/kg/d, rounded to nearest
250mg, in 2 or 3 divided doses. B6 as above.
Zinc salts – 75 mg/d in 3 divided doses.
(Dosing not well established for children <20kg body
weight and must be determined on an individual basis)
■
■
■
To confirm clinical and biochemical
improvement
Ensure compliance and efficacy of therapy
Identify adverse side effects in a timely fashion
D-Penicillamine
■ 24 hour urine copper 4 times per year initially,
then at least twice per year
■ Serum free copper 4 times per year initially,
then at least twice per year
■ CBC, liver biochemistries, INR, urinalysis: at 3,
6, 9, and 12 days, weekly for one month, twice
weekly for one month, biweekly for two
months, monthly for 6 months, every 3 months
for one year, every 6 months for 2 years, then
semi-annually
■ Urinalysis to screen for proteinuria and cells
Trientine
■ 24 hour urine copper 4 times per year initially,
then at least twice per year
■ Serum free copper 4 times per year initially,
then at least twice per year
■ CBC, liver biochemestries, INR, urinalysis: weekly
for 1 month, biweekly for 2 months, monthly
for 6 months, every 3 months for one year,
every 6 months for 2 years, then semi-annually
■ Urinalysis to screen for proteinuria and cells
Tetrathiomolybdate
■ Not established
Zinc
■
■
■
Evaluation for evidence of liver disease,
psychiatric and neurological symptoms.
Repeat exam for Kayser-Fleischer rings.
Careful history including possible changes in
behavior; or new psychiatric or neurological
symptoms; fatigability. History of new symptoms
related to liver disease: jaundice, ascites, edema.
■
■
■
24 hour urine copper and zinc twice in the first
6 months, every 6 months for 2 years, then
semi-annually
Serum free copper twice per year
CBC, liver biochemistries, INR: twice per year
Target Result Ranges
■ Serum Free Copper – 5 - 15µg/dL
■ 24 hour urine copper:
- Chelators – 200 – 500 µg/24 hours
- Zinc – <125 µg/24 hours
■ 24 hour urine zinc – >2.0 mg/d